I have been totally committed to a career as an academic biomedical researcher for the past ten years. At every opportunity, I have attempted to achieve the finest research and clinical training possible. Now, realizing the important contributions that molecular virology can make to the area of cancer research, I wish to take advantage of a Clinical Investigator Award to gain experience in this emerging field. I joined the faculty of the Department of Dermatology at The University of Pennsylvania two years ago. The Department is very much committed to my academic development, and I have spent most of my time in the laboratory of Dr. Nigel Fraser of The Wistar Institute. His lab has been consistently productive in the areas of Herpes Simplex virus type I (HSV-1) latency and pathogenesis, and has recently made inroads into the use of HSV-1 as gene therapy vectors. The overall goal of this proposal is to examine the therapeutic usefulness of neuroattenuated HSV-1 mutants for the therapy of brain tumors. This will be achieved in an intracranial murine melanoma model. These HSV-1 mutants replicate preferentially in tumor cells, and not within the generally post-mitotic cells of the nervous system. We will determine if this selective replication can be utilized to lyse tumor cells within the CNS, without harming the host. The experiments outlined in this proposal will allow us to correlate the genotype of each HSV-1 mutant with a therapeutic phenotype. Ultimately, these data will allow for the design of HSV- 1 mutants optimized for tumor therapy. Using a variety of complementary molecular techniques, we will perform detailed studies of the pathogenicity, specificity, and fate of candidate viruses subsequent to treatment of mice bearing intracranial melanoma. We will examine the role of host primary and secondary anti-viral immunity. We will also investigate two strategies for augmenting the effectiveness of this therapeutic approach. First we will combine viral therapy and ganciclovir, and second we will construct HSV-1 mutants that express cytokine genes within tumor cells using a technique of in vitro ligation- transfection. Our preliminary data show that this is a viable approach to brain tumor therapy, that offers hope for new therapeutic directions at a time when available therapies are completely inadequate. The expertise of the primary and secondary sponsors in virology and tumor biology respectively, and the collective resources of The Wistar Institute and the University of Pennsylvania, make this a perfect environment in which to perform these studies. I am confident that by the end of this training period, I will have the skills and experience necessary to be a first rate independent investigator, and will have advanced the field of experimental cancer therapy.